Alkylation of heterocyclic organic compounds



Patented May 19, 1953 ALKYLATION OF HETEROCYCLIC ORGANIC COMPOUNDSJulian M. Mavity, Hinsdale, Ill., assignor to Universal Oil ProductsCompany, Chicago, 111., a

corporation of Delaware No Drawing. Application July 29, 1948,

' Serial'No. 41,396

1 This application is a continuation in part of my copending applicationSerial No. 619,431, filed September 29, 1945, now Patent No. 2,461,326,April 12, 1949 i This invention relates to the catalytic interaction ofa heterocyclic organic compound with acompound capable of yielding ahydrocarbon radical. It is more particularly concerned with theproduction of certain alkyl heterocyclic organic compounds by reacting acompound such as a thiophene or a furan that contains a hydrogen-atomattached to the ring with an alkylating agent in the presence of acatalyst prepared by reacting boric acid and a metal halide of theFriedel-Crafts type.

Heterocyclic organic compounds, and particularly alkyl derivativesthereof, are increasing in use as intermediates in organic synthesis andin the production of plastics, germicides, medicinals, insecticides, andthe like. I have invented a new and improved process for producing suchcompounds.

In one embodiment my invention relates to a process which comprisesreacting a heterocyclic organic compound containing a substitutablehydrogen atom attached to the ring with a com-- pound capable ofyielding a hydrocarbon radical atcondensation conditions in the presenceof a catalyst prepared by reacting boric acid and a metal halide of theFriedel-Crafts type with the evolution of hydrogen halide. v a morespecific embodiment my invention relates to a process which comprisesreacting a thiophene containing a substitutable hydrogen atom. attachedto the ring with an alkylating agent at alkylating conditions in thepresence of a catalyst prepared by reacting boric acid and a metalhalide of the Friedel-Crafts type with the evolution of hydrogen halide.

The alkylatable material charged to my process is selected from theclass of heterocyclic organic compounds that are capable of condensingwith alkylating agents and the like. Two of the preferred species ofalkylatable materials comprise thiophenes and furans in which at leastone hydrogen atom is bound to the heterocyclic ring of four carbon atomsand one sulfur or oxygen atom. The various reactive thiophenes andfurans may be respectively represented by.

in which at least one of the groups R R R and R is a hydrogen atom andthe other R groups are selected from the group consistingofhydrogen,alkyl, cycloalkyl, aryl, aralkyl, alkaryl, and naphthyl.Nonhydrocarbon substituents such as a halogen, alkoxy, or an alkyl thioit claims. (Cl. 260-329) group may be present provided the thiophene orfuran contains at least one substitutable nuclear hydrogen atom. Lesspreferred species of alkylatable materials include indole and the like.

Alkylating agents capable of yielding an. alkyl group under theconditions of operation employed in the process are one type of compoundcapable of yielding hydrocarbon radicals that are utilizable in myprocess. Compounds of this type include both normally gaseous andnormally liquid olefins, particularly olefins containing more than twocarbon atoms per molecule. Such olefins include propylene, iso andnormal butylenes, iso and normal amylenes, methylcyclohexene, and thelike. Other alkylating agents include cycloparaffins containing three orfour carbon atoms in the ring, mercaptans, mineral acid esters such asalkyl halides, and alkoxy. compounds of the class consisting ofaliphatic alcohols, and esters of carboxylic acids. In general, thealkylating agents that are most easily reacted in my process comprisethose in which the double bond, or in which the substituent, such as thechlorine atom in alkyl chlorides, is attached to a tertiary carbon atom.Other compounds capable of yielding a hydrocarbon radical includediolefins and aromatic compounds in which a nuclear hydrogen atom hasbeen replaced by an olefinic hydrocarbon radical. Examples of sucharomatic compounds are styrene, alpha methyl styrene, and the like.

I have found that catalysts useful in promoting the condensation ofheterocyclic organic compounds containing a substitutable hydrogen atomattached to the ring with compounds capable of yielding hydrocarbonradicals may be made by interacting boric acid with a metal halide ofthe Friedel-Crafts type under such conditions that limited amounts ofhydrogen halide are evolved, which amounts generally are from about 0.5to about 2.0 molecular equivalents based upon the metal halide. Withsomeof the metal halides, a reaction starts as soon as the metal halideis mixed with boric acid. However, I usually prefer to heat suchmixtures to hasten said reaction. With other metal halides it isnecessary to heat the mixtures in order to initiate the reaction. It isapparent that since there are a number of Friedel-Crafts type metalhalides which may be interacted, a considerable number of alternativecatalysts may be made although such catalysts will not necessarily beequivalent in their action. Friedel-C'rafts type metal halides which maybe reacted with boric acid to- Iormcatalysts useful in the presentprocess in-. clude aluminum chloride, aluminum bromide, zinc chloride,zirconium chloride, ferric chloride, antimony chloride, bismuthchloride, and others. Substantially anhydrous aluminum chloride is theFriedel-Crafts type catalyst usually employed in the alkylation ofheterocyclic organic compounds. However, disadvantages accompany its usein some instances on account of its high degree of activity. Thus it hasa tendency to form undesirable complexes with unsaturated andheterocyclic compounds. However, by reacting proportioned mixtures of analuminum halide, such as aluminum chloride, and boricacid in accordancewith the present invention, catalysts of modified activities areobtained which may be utilized for promoting the alkylation ofheterocyclic compounds as herein set forth. These catalysts do not formsubstantial amounts of complexes with the reactants and, accordingly,they may be used in continuous processes over long periods of time withrelatively little contamination by such complexes so that in manyinstances the catalyst life is considerably longer than the life of thecorresponding aluminum halide in similar types of reactions. Anadditional advantage of these catalysts is that their solubility in theproducts of this reaction is con--' siderably less than that of metalhalide, such as aluminum chloride and aluminum bromide, and thus theusual step of recovering dissolved catalyst from the reaction productsoften can be eliminated.

The process of my invention may be carried out in batch operation byplacing a quantity of the catalyst in a reactor equipped with a stirringdevice, adding the heterocyclic organic compound, heating or cooling tothe reaction tcm= perature, slowly adding the alkylating agent whilemixing the contents of the reactor, and

recovering the product. However, the preferred method of operation is ofthe continuous type. In one mode ofcontinuous operation, the granularcatalyst, either alone or on a carrier, may be placed in a reactionchamber and preheated mixtures of the heterocyclic compound and thealkylating agent passed through the catalyst bed. If desired, a quantityof the hydrogen halide corresponding to the'catalyst may be charged tothe reaction zone as a promoter. The products from such a treatment maybe continuously frac tionated to separate theunreacted substances fromthe desired products.

The reactions herein described usually are car ried: out at temperaturesof from: about 20 to about 150 C. and under a pressure of from sub*stantially atmospheric to approximately 100' atmospheres. It ordinarilyis preferable to have present in the charging stock amolecular excess ofthe heterocyclic compound over thealkylating agent in order to minimizeside reactions.

The following examples are given to illustrate the method of preparingthe catalyst and the results obtained by the use of the present process,although the data presented are to be taken in an illustrative and notin a limitative sense, i. e., the data' are not to be taken as undulyrestricting the generally broad scope of the invention.

A. catalyst was prepared as follows:

20.64 grams moi) of ball mill ground, C. P. boric acid and 133.52 grams(1.0 men or fresh C. P'. anhydrous aluminum chloride "were inti mately'mixed by rotating in a mill equipped with agate balls for 1.23 hours.136.69 grams of the recovered mixture were transferred to an- 850 cc.glass bomb liner and heated in a rotating steel bomb at 200 C. for 1hour under an initial nitrogen pressure of 20 atmospheres; The nitrogenwas present to prevent sublimation. of the 4 aluminum chloride before ithad time to react with the b'oric acid. The material recovered from theliner weighed 124.63 grams; 12.06 grams of the starting material werelost as hydrogen chloride. The liner contents consisted of lumps of awhite" solid in the bottom of the liner with a hollow cylinder ofsimilar material resting on the lumps and a small amount of whitecrystalline sublimate at the top of the liner. There was a stronghydrogen chloride odor. The liner was cut just above the hollow cylinderand the hollow cylinder together with the lumps that were in the bottomof the liner were rapidly ground in amortar and stored in a glassstoppered bottle.

Example II Apparatusy -250 cc. 3 necked flask-with adraw off equippedwith a stopcock the bottom, and fitted with a 19 in. reflux condenser, acc. delibrate'd cylindrical dropping funnel, and a mercury sealedstirrer. Also, a-

in. and a '7 in. vacuum jacketed spiral wire filled column and a cc.Claissen flask.

Proccdura lnto astirred mixture of 12.1? grams of the catalyst preparedas described in Example I and 30 cc. of normal pentane, was in-=troduced approximates -or 42.10 grams of thiaphene. The temperature roseimmediately from 33 to-36 C. and the color of the catalyst changed fromwhite to red. The other of the thi'ophehe was mixed with 17.5 grams ofisoamylehes and this mixture was added dropwise over a 5- minute periodto the vigorously stirred mixture of catalyst, thiophene, and normalentane at 36C; The temperature of the reaction mi'xture'rose 2 C. duringthe additionof the first half" of the thiophene-isoamylene mixture andprobably would have gone even higher if the 35 C. water bath had notbeen removed. Later on the water bath had to be used again to maintain a3-7 reaction temperature. The stirring was con-- tinned for hours afterwhich approximately 100*gram s' of crushed ice were added to thereaction mixture, cooled to 5 (3., to decompose the catalyst. Theorganic layer. was separated from the aqueous layer and washedsuccessively with water, 10% sodium hydroxide, and water and dried oversodium sulfate. Distillation analysis of'the crude product showed that ayield of 21 Weight per cent of iscamylthio'phene based ontheisoamyl'enes' charged had" been produced in the reactidn.

Example III Isoamylenes are contacted with furair in the resence of aportion or the catalyst prepared as described under Example I.Gontactin'g takes place in a manner similar to that described in ExampleII. Inspection of the product shows that an appreciable yield Ofisoam'yl filiain has been" produced.

I claim as my invention:

1.; A process which comprises reacting a heterocyclic organic compoundselected rrom-the-group consisting of thiophenes and furanscontaining" asubstitutable hydrogen atom attached to a carbon atom of theheterocyclic ring with a compound capable of yielding a hydrocarbonradical at condensation conditions in the presence of a catalystprepared by reacting boric acid and a metal halide of theFriedel-"Craits type with the evolution of hydrogen halide.

2. A process which comprises reacting a hetero cyclic organic compoundselected from the group consisting of thiophenes and furans containing asubstitutable hydrogen atom attached to a carbon atom of theheterocyclic ring with an alkylating agent at alkylatlng conditions inthe presence of a catalyst prepared by reacting boric acid and a metalhalide of the Friedel-Crafts type with the evolution of hydrogen halide.

3. A process which comprises reacting a thiophene containing asubstitutable hydrogen atom attached to the ring with an alkylatingagent at alkylating conditions in the presence of a catalyst prepared byreacting boric acid and a metal halide of the Friedel-Crafts type withthe evolution of hydrogen halide.

4. A process which comprises reacting a thiophene containing asubstitutable hydrogen atom attached to the ring with an olefinichydrocarbon at alkylating conditions in the presence of a catalystprepared by reacting boric acid and a metal halide of the Friedel-Craftstype with the evolution of hydrogen halide.

5. A process which comprises reacting a thiophene containing asubstitutable hydrogen atom attached to the ring with a monoolefin atalkylating conditions in the presence of a catalyst prepared by reactingboric acid and a metal halide of the Friedel-Crafts type with theevolution of hydrogen halide.

6. A process which comprises reacting a thiophene containing asubstitutable hydrogen atom attached to the ring with a monoolefincontaining more than two carbon atoms per molecule at alkylatingconditions in the presence of a catalyst prepared by reacting boric acidand a metal halide of the Friedel-Craits type with the evolution ofhydrogen halide.

'alkylating conditions in the presence of a catalyst prepared byreacting boric acid and a metal halide of the Friedel-Craits type withthe evolution of hydrogen halide.

9. A process which comprises reacting a furan containing a substitutablehydrogen atom attached to the ring with an alkylating agent atalkylating conditions in the presence of a catalyst prepared by reactingboric acid and a metal halide of the Friedel-Crafts type with theevolution of hydrogen halide.

10. A process which comprises reacting a furan containing asubstitutable hydrogen atom attached to the ring with an olefinichydrocarbon at alkylating conditions in the presence of a catalystprepared by reacting boric acid and a metal halide of the Friedel-Craftstype with the evolution of hydrogen halide.

11. A process which comprises reacting a furan containing asubstitutable hydrogen atom attached to the ring with a monoolefin atalkylating conditions in the presence of a catalyst prepared by reactingboric acid and a metal halide of the Friedel-Crafts type with theevolution of hydrogen halide.

12. A process which comprises reacting a furan containing asubstitutable hydrogen atom attached to the ring with a monoolefincontaining more than two carbon atoms per molecule at alkylatingconditions in the presence of a catalyst 6 prepared by reacting boricacid and a metal halide of the Friedel-Crafts type with the evolution ofhydrogen halide.

13. A process which comprises reacting a furan containing asubstitutable hydrogen atom attached to the ring with an isoolefin atalkylating conditions in the presence of a catalyst prepared by reactingboric acid and a metal halide of the Fried el-Crafts type with theevolution of hydrogen halide.

14. A process which comprises reacting a furan containing asubstitutable hydrogen atom attached to the ring with an isoamylene atalkylating conditions in the presence of a catalyst prepared by reactingboric acid and a metal halide of the Friedel-Crafts type with theevolution of hydrogen halide.

15. A process which comprises reacting a heterocyclic organic compoundselected from the group consisting of thiophenes and furans containing asubstitutable hydrogen atom attached to a carbon atom of theheterocyclic ring with an alkylating agent at a temperature of fromabout 20 C. to about 150 C. and under a pressure of from substantiallyatmospheric to approximately atmospheres in the presence of a catalystprepared by reacting boric acid and a metal halide of the Friedel-Craftstype with the evolution of hydrogen halide.

16. A process which comprises reacting a heterocyclic organic compoundselected from the group consisting of thiophenes and furans containing asubstitutable hydrogen atom attached to a carbon atom of theheterocyclic ring with an alkylating agent at a temperature of fromabout 20 C. to about C. and under a pressure of from substantiallyatmospheric to approximately 100 atmospheres in the presence of acatalyst prepared by reacting boric acid and an aluminum halide with theevolution of hydrogen halide.

17. A process which comprises reacting a heterocyclic organic compoundselected from the group consisting of thiophenes and furans containing asubstitutable hydrogen atom attached to a carbon atom of theheterocyclic ring with an alkylating agent at a temperature of fromabout 20 C. to about 150 C. and under a pressure of from substantiallyatmospheric to approximately 100 atmospheres in the presence of acatalyst prepared by reacting boric acid and aluminum chloride with theevolution of hydrogen chloride.

JULIAN M. MAVI'IY.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,141,611 Malishev Dec. 27, 1938 2,341,362 Connolly Feb. 8,1944 2,396,144 Anderson Mar. 5, 1946 2,407,918 Burgin Sept. 17, 19462,408,167 Hepp Sept. 24, 1946 2,432,482 Matuszak Dec. 9, 1947 2,467,326Mavity Apr. 12, 1949 OTHER REFERENCES Galloway: Chemical Review, vol.17, page 376 (1935).

Richter: Organic Chemistry, Wiley (1938), pages 649-650.

Berkman: Catalysis, Rheinhold Publishing Corporation (1940), page 953.

1. A PROCESS WHICH COMPRISES REACTING A HETEROCYCLIC ORGANIC COMPOUNDSELECTED FROM THE GROUP CONSISTING OF THIOPHENES AND FURANS CONTAINING ASUBSTITUTABLE HYDROGEN ATOM ATTACHED TO A CARBON ATOM OF THEHETEROCYCLIC RING WITH A COMPOUND CAPABLE OF YIELDING A HYDROCARBONRADICAL AT CONDENSATION CONDITIONS IN THE PRESENCE OF A CATALYSTPREPARED BY REACTING BORIC ACID AND A METAL HALIDE OF THE FRIEDEL-CRAFTSTYPE WITH THE EVOLUTION OF HYDROGEN HALIDE.